Proprotein convertase subtilisin kexin type 9 (PCSK9) is a serine protease recognized for involvement in the regulation of levels of low-density lipoprotein receptor (LDL-R) protein. In vitro experiments have shown that the addition of PCSK9 to HepG2 cells lowers the levels of the cell surface LDL-R. In addition to this observation, experiments with mice have demonstrated that increasing the concentration of PCSK9 in blood plasma results in a decrease in LDL-R protein in the liver. In addition to PCSK9 mouse knockouts having increased levels of LDL-R in the liver, various PCSK9 mutations have been identified (in several species) that result either in increased or decreased plasma levels of LDL. Experiments have demonstrated a specific interaction between PCSK9 and LDL-R and that the proteins co-immunofluoresce throughout the endosomal pathway.
There is an interest in the art in developing inhibitors of PCSK9 since this gene is a valuable target for treatment of lipid disorders such as hyperlipidemia. The present invention addresses this need by providing a new method for inhibiting proteolytic cleavage and activation of PCSK9.